The pandemic is gone but its consequences are here to stay: avascular necrosis following corticosteroids administration for severe COVID-19

Background In patients with COVID-19 infection and respiratory insufficiency, corticosteroid (CCS) administration is recommended. Among the wide range of complications and interactions, time-limited high-dose CCS administration might promote avascular necrosis (AVN) in a cumulative dose. This systematic review updated the current evidence and characterises the trend of AVN following time-limited high-dose CCS administration in patients who had severe COVID-19, discussing management strategies and outcomes. Methods This systematic review was conducted according to the 2020 PRISMA statement. In October 2023, the following databases were accessed: PubMed, Web of Science, Google Scholar, and Scopus restricting the search to the years 2019 to 2023. All the clinical studies which investigated the association between time-limited high-dose CCS administration in patients with severe COVID-19 infection and AVN were accessed. Results A total of 245 patients (9 studies) who experienced AVN following COVID-19 were included in the present investigation. 26% (63 of 245 included patients) were women. The mean age of the patients was 42.9 ± 17.7 years. Four studies focused on AVN of the hip and two on the knee, and the other studies included patients with AVN from mixed areas of the body (spine, pelvis, and shoulder). The mean time elapsed from COVID-19 infection to the development of symptomatic AVN was 79.4 ± 59.2 days (range, 14 to 166 days). Conclusion It is possible that even time-limited high-dose CCS administration in patients with severe COVID-19 infection increased the incidence of AVN. The mean time elapsed from COVID-19 infection to the development of symptomatic AVN was approximately 80 days. Given the high risk of bias in all the included studies, the quality of recommendations of the present investigation is low, and no reliable conclusion can be inferred.


Introduction
The Coronavirus disease-2019 (COVID-19) emerged in November 2019 in Wuhan, China, and was declared by the World Health Organisation (WHO) a pandemic a few months later [1,2].Other coronaviruses caused epidemics in the past decades, including Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) [3,4].The COVID-19 pandemic imposed healthcare systems worldwide with new challenges and considerable organisational efforts [5][6][7][8][9][10].Often far-reaching process changes, such as the management of patient flows, had to be implemented in everyday clinical practice within a very short period [11][12][13][14][15].The management of COVID-19 is complex and, to date, no shared guidelines exist [16][17][18].In patients with COVID-19 infection and respiratory insufficiency, corticosteroids (CCS) administration is recommended [19][20][21].CCS administration is indicated in patients receiving oxygen therapy or invasive mechanical ventilation [22][23][24][25].CCS immunomodulates the acute cytokine storm, which is pivotal in the management of COVID-19 [22,24].However, depending on the timing of administration, the immunomodulation promoted by CCS might be beneficial (if hyperactivation had already occurred) or detrimental in the case of early immune response inhibition [26][27][28].No benefit of CCS administration has been demonstrated in patients with no critical symptoms [22,29,30].However, CCS administration is associated with several complications, including immunodeficiency, diabetes, hypertension, obesity, and thromboembolism [31][32][33].Given the high rate of CCS administration and the onset of related complications, the European Society of Endocrinology (ESE) has recently commissioned an urgent clinical guidance document on CCS administration in a COVID-19 period [34].Among this wide range of complications and interactions, time-limited high-dose CCS administration might promote avascular necrosis (AVN) in a cumulative dose [35][36][37].AVN is characterised by the refractory and progressive compromise of bone architecture and vascularisation, which leads to morphological remodelling, premature osteoarthritis (OA), persistent pain, and loss of function [38][39][40][41][42].This systematic review updated current evidence and characterised the trend of AVN following time-limited high-dose CCS administration in patients who had severe COVID-19, investigating the time elapsed from COVID-19 infection and the development of symptomatic AVN, and discussing management strategies and related outcomes.

Eligibility criteria
All the clinical studies which investigated the association between time-limited high-dose CCS administration in patients with severe COVID-19 infection and AVN were accessed.According to the author's language capabilities, articles in English, German, Italian, French and Spanish were eligible.Studies with levels I to IV of evidence, according to the Oxford Centre of Evidence-Based Medicine [43], were considered.Posters, abstracts, comments, editorials, opinions, and reviews were not eligible.Only investigations which reported quantitative data on the association between timelimited high-dose CCS administration in patients with severe COVID-19 infection and AVN were eligible.

Search strategy
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the 2020 PRISMA statement [44].The PICO algorithm was preliminarily set out:

Selection and data collection
Two authors (FM & TS) independently performed the database search.All the resulting titles were screened, and if suitable, the abstract was accessed.The full text of the abstracts which matched the topic was accessed.The bibliography of the full-text articles was also screened for inclusion.Any disagreements were discussed and settled by a third senior author (NM).

Data items
Two authors (FM & TS) independently performed data extraction.Studies generalities (author, year, name of the journal, nature of the study design, and purpose of the study) and data on patient demographics (study size, number of women, and mean age of the patients) were retrieved.Data on the type of CCS, severity of infection, main conclusion, and the time elapsed from COVID-19 infection and the diagnosis of symptomatic AVN were collected.

Study risk of bias assessment
Two reviewers (TS & RDA) independently performed the methodological quality assessment of the extracted studies.Disagreements were solved by a third senior author (NM).The study risk of bias assessment was conducted in accordance with the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions [45].The risk of bias of the software Review Manager 5.3 (The Nordic Cochrane Collaboration, Copenhagen) was used for Randomised Control Trials (RCTs).The Risk of Bias in Nonrandomised Studies of Interventions (ROBINS-I) tool was used for non-RCTs [46].

Statistical analysis
For descriptive statistics, the SPSS software version 25 (IBM, International Business Machines Corp, Armonk, US) was used.

Study selection
A total of 1221 articles resulted from the literature search.Of them, 277 were duplicates.A further 757 articles were excluded for the reasons: no reported data on COVID-19 patients (N = 158), no reported data on AVN (N = 571), type of study (N = 178), did not report quantitative data on the outcome of interest (N = 28).Finally, 9 articles were included in the present study.The flow chart of the literature search is shown in Fig. 1.

Study risk of bias assessment
The ROBINS-I score evidenced an overall high risk of bias.Most studies were retrospective case series and no RCT was available, with a high risk of selection, detection and performance biases.All the risks of bias investigated in the ROBINS-I score were serious and critical (Table 1).

Study characteristics and results of individual studies
A total of 245 patients who experienced AVN following COVID-19 were included in the present investigation.26% (63 of 245 included patients) were women.The mean age of the patients was 42.9 ± 17.7 years.Four studies [50,51,53,54], overall involving 228 patients, focused on AVN of the hip, and two studies (5 patients) [47,48] focused exclusively on the knee.The other studies included patients with AVN deriving from mixed areas of the body (spine, pelvis, shoulder) [49,52,55].Study generalities and data of the patients are shown in Table 2.
Table 3 reports the aims of the studies and the main results of the included studies.The mean time elapsed from COVID-19 infection to the development of symptomatic AVN was 79.4 ± 59.2 days (range, 14 to 166 days).

Discussion
According to the main findings of the present systematic review, there is evidence of increased incidence of AVN after the use of time-limited high-dose CCS therapy in patients with COVID-19 infection.The mean time   4).However, no study reported cases of AVN among time-limited highdose CCS-treated patients.On the other hand, we were able to identify for inclusion only articles with low levels of evidence in the present study.In this context, no high-quality recommendations can be inferred.Further, high-quality investigations and multi-centre studies are required to establish the actual incidence of AVN following time-limited high-dose CCS therapy in patients with COVID-19 infection.
Previous evidence demonstrated that the use of CCS and their association with AVN is related to cumulative dose [35,[72][73][74].However, there is no consensus on their safety threshold.In a recent RCT, the administration of Dexamethasone 6 mg daily for 10 days (600 mg of cumulative dose) in COVID-19 patients was associated with a reduction of the need for mechanical ventilation and 28-day mortality [25,61].This dose regime is well below the cumulative dose thresholds described in much of the literature (cumulative dose of 2 g prednisone or its equivalent) [75,76].However, there is growing evidence that, if the clinical conditions deteriorate or patients are admitted to critical care, greater pulse doses of CCS (up to 125 mg per day) should be administered [77][78][79][80].However, AVN has been reported even at much lower dose thresholds [81][82][83].In a recent meta-analysis of 10 studies (1137 recovered patients with SARS) the risk of AVN was low if the cumulative dose of CCS (methylprednisolone) was ≤ 5 g.Greater cumulative doses of 5 g to 10 g were at high risk for AVN [84].
In those patients, total hip arthroplasty is considered the last resort in the management of AVN [121].
We acknowledge several limitations of this study.Given the high risk of bias in all the included studies, the quality of recommendations of the present investigation is low, and no definite conclusions can be inferred.Given the lack of information on administration protocol and timing of CCS, additional subgroup analyses were not performed.In one included study, only 6% of the entire cohort of patients who had severe COVID-19 developed AVN following time-limited high-dose CCS administration [53].The definition of severe COVID was not clearly stated in most articles, which poses limits to properly defining the study population.The current literature will benefit future highquality investigations.Most studies were case reports, with a limited number of patients and not using validated patient-reported outcome measures (PROMs).The surgical procedures and rehabilitation protocols were also biased in most studies, as were general health measures.COVID-19-associated therapies and severity, comorbidities and patient characteristics were also seldom described in most studies.Most patients affected by AVN are young and active, which makes the management of such a potentially devastating condition troublesome.The current treatment strategies are limited, with unpredictable results; despite some new treatment modalities having been introduced with promising results [122,123], prevention, early diagnosis, and early treatment remain the way to manage AVN.The type of CCS used to manage respiratory insufficiency and the severity of the COVID-19 infection were not reported by most authors.Moreover, the severity and progression of AVN were not classified using validated

Conclusion
Some evidence supports that even time-limited highdose CCS administration in patients with COVID-19 infection increased the incidence of AVN.The mean time elapsed from COVID-19 infection to the development of symptomatic AVN was approximately of 80 days.Given the high risk of bias in all the included studies, the quality of recommendations of the present investigation is low, and no reliable conclusion can be inferred.

The search was restricted to the years 2019 to 2023. The following keywords were used in combi- nation using the Boolean operators AND/OR: (COVID OR COVID-19 OR pandemic) AND (avascular osteone- crosis OR aseptic osteonecrosis OR osteonecrosis) AND (pain OR outcome OR incidence OR prevalence OR
symptoms) AND (steroids OR corticosteroids OR cortisone OR dexamethasone OR hydrocortisone OR prednisolone OR betamethasone).

Table 1
ROBINS-I of the included studies

Table 3
Main findings of the included studies (AVN: avascular necrosis; CCS: corticosteroids; MRI: magnetic resonance imaging)

Table 4
Clinical investigations exploring the time-limited high-dose CCS administration in patients with COVID-19 infection receiving oxygen therapy or invasive mechanical ventilationThe analysis included 13 articles for a total of 10,748 patients treated with steroids for COVID-19.Eleven studies were retrospective, one open-label non-RCT, and one prospective controlled, open-label trial.The steroids used varied from Dexamethasone, Prednisone, or Methylprednisolone.No case of AVN among time-limited highdose CCS-treated patients was reported , such as the Association Research Circulation Osseous (ARCO) for the femoral head. classification